Calcitonin (CT) and parathyroid hormone (PTH) are promising therapeutic agents for the prevention and reversal of postmenopausal osteoporosis, but their clinical utility is compromised by high cost and the need for frequent parenteral administration. The proposed research involves testing a novel hormone delivery system in which CT and PTH are incorporated in biodegradable microspheres, a form allowing weekly rather than daily injections of the hormones. The ovariectomized (OVX) rat will serve as an animal model of estrogen deficiency for comparative studies of the bone protective effects of daily or alternate day injections of free hormones and weekly injections of hormone microspheres. In the first experiment, CT will be evaluated for the prevention of osteopenia in the estrogen-deficient state. OVX rats will be treated for 30, 60, or 90 day periods with free CT on alternate days or weekly with CT microspheres formulated for sustained or pulsatile release. In the second experiment, PTH will be evaluated for restoration of lost bone mass in the estrogen-deficient state. OVX rats will be untreated for the first month after surgery to allow for the development of moderate osteopenia. These animals will then be treated daily for 30, 60, or 90 day periods with free PTH or weekly with PTH micro spheres formulated for sustained or pulsatile release. In the third experiment, doses and formulations of CT and PTH microspheres proven to be effective in the first two experiments will be used for long-term treatments to determine whether the beneficial skeletal effects of the hormone microspheres can be maintained in aged OVX rats over an 18 month period. The skeletal effects of the various treatments will be studied in cancellous bone tissue of the proximal tibial metaphysis and lumbar vertebral body as well as cortical bone of the tibial diaphysis by standard bone histomorphometric techniques. Changes in cancellous and cortical bone mass as well as histologic indices of bone formation, resorption, and mineralization will be measured. Serum biochemistry will be performed to determine the effects of CT and PTH treatment on systemic bone metabolism and serum mineral and hormone levels. It is hypothesized that l) weekly injections of CT and PTH microspheres will be as effective as daily or alternate day injections of the free hormones for the prevention and reversal of osteopenia in the estrogen-deplete state, and 2) CT and PTH microspheres formulated for pulsatile release will be more effective in this regard than hormone microspheres formulated for sustained release. Validation of these hypotheses would provide a rationale for clinical trials of improved hormone therapies for the prevention and reversal of postmenopausal osteoporosis.